Project 1- Summary/Abstract Nearly 200 million people in the world, including ~57 million in Bangladesh and ~17 million in the United States (US), are chronically exposed to inorganic arsenic (As). As part of the Columbia University SRP, we established the Health Effects of Arsenic Longitudinal Study (HEALS)?a large prospective cohort study based on individual-level data among a population exposed to a wide range of inorganic As from drinking water in Araihazar, Bangladesh. Over the past 15 years, using a population-based sampling frame, we recruited 35,050 men and women (with >95% response rates) and collected detailed questionnaires, clinical data, and biospecimen samples at baseline recruitment as well as every two years subsequently. Approximately 73% of participants are exposed to water As at low-to-moderate doses (<100 g/L). Through a dedicated medical clinic established by Columbia University and The University of Chicago that exclusively serves the HEALS participants, we have also developed an effective mechanism of following the cohort, especially for detecting incidence of respiratory and cardiovascular disorders. In this proposal, with up to 21 years follow-up, we propose to prospectively evaluate i) the effects of As exposure, measured in water, urine, and rice intake, on incidence of cardiovascular disease (CVD) and CVD subtypes, chronic non-malignant respiratory diseases (CNRD) and CNRD subtypes, and diabetes mellitus (DM); ii) the effects of specific urinary As species on the incidence of CVD, CNRD, DM, and their certain subtypes; iii) the effects of As exposure, measured in water, urine, and rice, on biomarkers and subclinical measures of CVD, CNRD and DM. We will evaluate these association also in participants exposed to water As at low-to-moderate doses (<100 g/L). We also plan to conduct individual level meta-analyses pooling data from HEALS and other major population studies in USA (Strong Heart Study, New Hampshire Arsenic Study, and San Luis Valley Study), Taiwan (Taiwanese Arsenic Study) and China (Inner Mongolia Arsenic Study), to examine full dose-response relationship between As exposure and CVD incidence and mortality. The National Research Council (NRC) has identified non-cancer outcomes as a high-priority outcome for As exposure. Findings from HEALS will have major impact on the health of As-exposed populations globally.